The present invention concerns novel compounds which are 5-hydroxy-2-pyrimidinylmethylene oxaza heterocycles, which are five, six, and seven membered rings belonging to the 3-isoxazolidinone, 2H-1,2-oxazin 3(4H) one and 3-isoxazepinone class, and pharmaceutically acceptable acid addition or base salts thereof, pharmaceutical compositions and methods of use therefor. The compounds of the present invention have activity as inhibitors of 5-lipoxygenase and/or cyclooxygenase providing treatment of conditions advantageously affected by such inhibition including inflammation, arthritis, pain, fever, and particularly rheumatoid arthritis, osteoarthritis, other inflammatory conditions, psoriasis, allergic diseases, asthma, inflammatory bowel disease, GI ulcers, cardiovascular conditions, including ischemic heart disease and atherosclerosis, and ischemia-induced cell damage, particularly brain damage caused by stroke. They can also be used topically for treating acne, sunburn, psoriasis, and eczema. Also included are leukotriene mediated pulmonary, gastrointestinal, inflammatory, dermatological, and cardiovascular conditions. The disclosed compounds also have potential utility as antioxidants. The preferred use is in treating inflammatory conditions. Thus, the present invention is also a pharmaceutical composition or method of manufacturing a pharmaceutical composition for the use of treating the noted conditions.
3,5-Di-tertiarybutyl-4-hydroxyphenyl substituted oxaza heterocycles are known to provide in vivo antiinflammatory activity as described in U.S. Pat. No. 4,892,870.
Various 5-hydroxypyrimidines are described in copending U.S. application Ser. Nos. Numbers 648,114, and 648,115 of Jan. 31, 1991, No. 756,400 of Sep. 9, 1991, No. 840,360 of Feb. 24, 1992, and No. 847,511 of Mar. 6, 1992. These compounds are also active as inhibitors of 5-lipoxygenase and/or cyclooxygenase. Such disclosed pyrimidines may also be substituted at the 4- and/or 6- positions with various alkyl groups. Yet none show the present 2-substituted oxaza heterocycles interrupted by vinyl.